The hypothalamic hormone gonadotropin-releasing hormone (GnRH) displays gender-specific actions. Pituitary responsiveness to GnRH is increased in females compared to males. GnRH is now known to be produced by the immune system and to exert immunological actions. We have established that female mice exhibit more vigorous T lymphocyte proliferative responses to GnRH than male mice. Our central hypothesis is that the increase in immune responsiveness to GnRH in females plays a pivotal role in the enhanced immune function in females and the increased incidence of autoimmune diseases in females. We have demonstrated that GnRH exacerbates lupus in a mouse model in a gender specific manner: only females respond to GnRH with exacerbation of disease. Subsequent studies from our laboratory suggest that the enhanced immunological responsiveness to GnRH seen in female mice relates to increases in the expression of the signal transducers through which GnRH acts, namely, the G proteins, Galphas and Galphaq/11. Further studies from our lab have revealed that females display enhanced responsiveness to other hormones whose actions are mediated by stimulatory G proteins. We now hypothesize that: 1) Increased responsiveness to GnRH in female mice contributes to enhanced B and T lymphocyte function in females and to gender differences in cytokine production; 2) Increased production of or responsiveness to GnRH in female mice contributes to the increased expression of S.L.E. in female mice; 3) Increased expression of stimulatory G proteins in females contributes to the increased responsiveness to GnRH, PTH, and beta-adrenergic agents in females compared to males. 4) Exposure to GnRH, progesterone, and or/estrogen increases the responsiveness to GnRH and increases the activity of specific stimulatory G proteins in immune cells and that exposure to GnRH antagonists/androgens decreases the responsiveness to GnRH and decreases quantities and/or activity of specific stimulatory G proteins in immune cells. G proteins are the signal transducers for a variety of hormones, including CRH, ACTH, LH, FSH, TSH, and PTH. If gender differences in the ubiquitously expressed G proteins exist, they may play a role in a variety of other diseases affecting females predominantly, including osteoporosis, precocious puberty and McCune Albright syndrome.